Higher Disease Control Rate Research Articles

Abstract 2492: Association of TP53 and LRP1B co-mutation status with response to immunotherapy in lung squamous cell carcinoma

Abstract Background: Immunotherapy can induce a long response in part patients of lung squamous cell carcinoma (LUSC). And accurate biomarkers are needed for suitable populations. As important tumor suppressor, tumor protein p53 (TP53) and low density lipoprotein receptor-related protein 1B (LRP1B) genes may be associated with immunogenicity. However, the interaction of TP53 and LRP1B and its potential association with response to immunotherapy are not fully understood in LUSC. Methods: Three cohorts were divided into four groups, respectively (A: TP53mut and LRP1Bmut, B: TP53mut and LRP1Bwild, C: TP53wild and LRP1Bmut, D: TP53wild and LRP1Bwild). 525 LUSCs form Geneplus database which performed next-generation sequencing were assessed the differences of genomic landscape, tumor mutation burden (TMB), and PD-L1 expression in four groups (cohort 1). TCGA-LUSC RNA data (n=466) from cBioPortal were used to evaluate immune cell infiltration thought single sample gene set enrichment analysis (cohort 2). The LUSCs (n=125) which received immunotherapy of POPLAR and OAK cohort were used to evaluate the efficacy of immunotherapy in four groups (cohort 3). Results: The proportion of patients in A, B, C and D groups of cohort 1 was 26%, 59%, 2%, 13%, respectively, suggesting that most patients with LRP1B mutation also carry TP53 mutation (98.6%) in LUSC. This similar ratio is 88.2% in cohort 2 and 74.3% in cohort 3. For group A, the most common mutated gene except TP53 and LRP1B was CDKN2A (31%). Group B was MLL2(28%). Group C was CDKN2A (33%). Group D was FAT1 (13%). The median TMB was 14.4 mutations/Mb (2.9-80.0) in group A, 9.8 (0.96-95.0) in group B, 11.5 (2-25) in group C, 3.8 (0.96-18.2) in group D. TP53 and LRP1B co-mutation had a highest TMB compared with the other three groups in all cohorts, while TP53wild and LRP1Bwild completely opposite. In cohort 1, PD-L1 expression had no significant difference in four groups. In cohort 3, progression-free survival (PFS) was longer in group D compared with the other three groups (p = 0.047, A: 1.5m, B: 1.6m, C: 2.1m, D: 4.2m). The same trend on overall survival (OS) were found but it was not significant. Group D also had a higher disease control rate (A: 50%, B: 46%, C: 44%, D: 69%). We than divide into two groups (D vs Other) to compare PFS and OS. It showed that group D had a prolonged PFS (p = 0.02) and OS (p = 0.03). Multivariate cox regression analysis showed that the results were independent of TMB, gender and age. Analysis of immune cell infiltration in cohort 2 showed that the better outcomes of group D might associated with elevated infiltrations of activated dendritic cell and activated CD8 T cell. Conclusion: TP53mut and LRP1Bmut, which accounted for a high proportion of LUSC, was associated with high TMB. And TP53wild and LRP1Bwild has better anti-PD-L1 outcome in LUSC. This might be related with a stronger activated dendritic cell and activated CD8 T cell infiltration despite lower TMB. Citation Format: Jiangyong Yu, Zhipeng Zhou, Ping Zhang, Pansong Li, Xu Li, Min Tang, Nannan Fan, Xiaonan Wu, Xin Nie, Xiaoyan Chen, Di Ma, Xi Chen, Yanfang Guan, Xuefeng Xia, Ling Yang, Xin Yi, Lin Li. Association of TP53 and LRP1B co-mutation status with response to immunotherapy in lung squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2492.

Current and future research efforts in oligometastatic non-small cell lung cancer-a systematic review.

BackgroundMajor progresses in the systemic treatment of non-small cell lung cancer (NSCLC) were obtained during the last decade, including the use of immunotherapy and tyrosine kinase inhibitors (TKIs), with impressive results in terms of response and survival rates. Moreover, novel imaging and radiotherapy techniques have allowed the development of stereotactic body radiotherapy (SBRT), with high rates of local disease control and minimal toxicity. These factors propelled the use of combined systemic and local treatment strategies in patients with a low burden of metastases—the oligometastatic disease (OMD).MethodsWe systematically review the evidence from prospective randomized and non-randomized trials on local ablative therapy for OMD NSCLC published until June 2020. In addition, we present a review of the ongoing and/or recruiting trials in the field.ResultsWe included 16 articles, reporting on 14 prospective clinical trials, starting from the pilot trial conducted in the early 2000’s to the recent randomized trials that have showed benefits in survival. We found 24 ongoing trials, which combine multiple local ablative regimens with new systemic therapies, such as new generation TKIs and immunotherapy.DiscussionDespite these vast current and ongoing prospective research efforts, there are several issues that impair the generalizability of their findings. These include the heterogeneous definition of OMD, trial design, staging, patient selection, tumor mutational status and treatments used, which may limit their applicability in the clinical practice.

Phase I/IB Study of Azacitidine and Hedgehog Pathway Inhibition with Sonidegib (LDE225) in Myeloid Malignancies

Background: Lower intensity therapies for patients (pts) with myeloid malignancies (AML, MDS, CMML, MPNs) are beneficial, but suboptimal despite the emergence of potentially active new agents. Even after an initial response to hypomethylating agents (HMAs) [5-Azacitidine (AZA) or decitabine], the majority of patients fail treatment. In large-scale RNAi screens we identified Hedgehog pathway (HP) genes as a potential rational combination to overcome a priori and acquired HMA resistance. Herein we report the first analysis of the final study results of the oral smoothened (SMO) inhibitor, Sonidegib (LDE225) in combination with AZA in 63 pts treated on a Phase 1/1B (Ph1/1B) trial.Methods: Ph1 (3+3) dose escalation and Ph1B (expansion cohort) study to determine the MTD (Ph1) and best overall response (Ph1B) of Sonidegib (SON) combined with AZA. 2nd endpoints included AEs, DOR, TTP, OS, time to AML for MDS pts and QOL. Pts with untreated and relapsed/refractory (rel/ref) AML, CMML, MDS, MDS/MPN overlap (MDS/MPN) or myelofibrosis (MF) were eligible. SON was started at dose level (DL) 0 at 400mg oral daily continuously (28 day cycle) and AZA at 75mg/m2 x 7 days or days 5-2-2 with dose adjustment per label. Dose-limiting toxicity (DLT) in Ph1 was assessed after 42 days at steady-state concentrations of SON. Pharmacokinetics were not performed.Results:Study population:From 05/2014 to 05/2017 (data cut-off) 63 pts were enrolled and followed for outcome: 10 pts were treated on the Ph1 and 52 in Ph1B part of the trial (1 pt withdrew). Median age was 72.5 years (range 39-86) and 66% pts were male. ECOG 0, 1 and 2 are 34%, 61% and 5% respectively. 45% (n=28) were newly diagnosed and 55% (n=34) rel/ref pts. 38 pts (61%) had AML and 13 of the 15 newly diagnosed/untreated AML pts had 2nd AML due to AHD; 23/38 pts had rel/ref AML. For all AML pts 21/38 were intermediate risk and 16/38 had unfavorable cytogenetics (1/38 unknown). 18 pts (29%) had MDS, all in the Intermediate, High or Very High risk status (IPSS-R), 4 (6.5%) had CMML and 2 pts MF.Dose levels, treatment administration and follow up: 6 pts were treated at DL0 SON 400mg/day continuously with AZA and 1 DLT of CPK elevation observed, while another pt had grade 4 neutropenia (at that time included in DLT definition, later removed). Due to overall tolerance of the combination at DL0 and investigator assessment, despite only 1/6 formal DLTs, DL -1 at SON 200mg x28 days was explored without further DLT (n=4 pts) and 52 pts accrued on Ph1B. For the 56 pts treated at the MTD dose of SON 200mg (Ph1B=52 and Ph1=4 pts), after a median of 14.5 months follow up, 218 cycles have been administered (median 3 cycles-range 1-25 ms). Median doses for SON and AZA were 200mg and 75mg/m2 respectively. 12.5% and 18% of pts had dose adjustments and 71.4% (i.e. missed only 1 dose) and 18% dose omissions at least once for SON and AZA respectively. 19/56 (34%) of pts are alive.Safety and Tolerability : Of 56 pts treated at MTD dose100% experienced at least one grade (gr) 3 AE and 52 (93%) had a gr 4 AE regardless of attribution. 96% and 91% had a gr 3 and gr 4 Heme AE and 73% and 20% had a gr 3 and gr 4 Non-Hem AE respectively. Gr 3/4 AEs were as expected for either drug and the diseases under study and were: thrombocytopenia (n=51), neutropenia (47), anemia (43), leukopenia (41). Most common gr 1/2 AEs were: fatigue (n=48), constipation (29), nausea/cough (each 24), insomnia (19), diarrhea (18), abdominal pain (16). 4/56 pts died on study deemed not drug related (cardiac arrest, MOF, neoplasm, sudden death).Efficacy: With a median follow up of 14.5 ms the best response outcome for untreated AML/MDS patients was 23.1% and for rel/ref 7.1%. However, the rate of SD (NR) was remarkably high particularly in the rel/ref AML population at 76% (16/21 pts, 2 not yet assessed). This high disease control rate was reflected in an OS of 7.6 ms (4.6-NE) in rel/ref AML, the majority of which failed previous HMAs .Conclusion: In this, to date largest SMO inhibitor/HMA combination trial, the oral SMO inhibitor SON was safe with full dose AZA in untreated and previously treated AML, MDS/CMML and MF pts. Although remission rates are not superior to single agent AZA in the heavily pre-treated and advanced myeloid malignancy population, the OS and lack of progression are encouraging, particular in the rel/ ref AML population indicating that SMO/Hh pathway inhibition may add to HMA efficacy. Predictive biomarker studies are ongoing. DisclosuresMesa:Ariad: Consultancy; Galena Biopharma, Inc.: Consultancy; CTI BioPharma Corp.: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; Promedico: Research Funding; Gilead Sciences, Inc.: Research Funding; Celgene Corporation: Research Funding.

Sequential Regimen with Thiotepa, Cyclophosphamide, Etoposide, Fludarabine and Busulfan in Allogeneic Stem Cell Transplantation for the Treatment of Relapsed and Refractory Hematological Malignancies

INTRODUCTION: Relapsed / Refractory leukemia and lymphoma (R/R, L/L) patients have a very poor prognosis despite all the well-known therapeutic strategies. Sequential conditioning followed by allogeneic stem cell transplantation (allo-SCT) provides an efficient disease control in those high risk patients.PATIENTS AND METHODS: we conducted a retrospective study at the American University of Beirut medical center (AUBMC) to assess the safety and efficacy of sequential conditioning in patients with R/R, L/L undergoing allo-SCT. We included 14 consecutive patients with (R/R, L/L) who received sequential conditioning followed by allogeneic stem cell transplantation (allo-SCT) from either matched related or haploidentical donors from April 2015 to May 2017. At time of transplantation patients included in the study were either in progressive disease (PD) or complete remission 2 (CR2), or partial remission (PR) after many lines of treatment. The study was approved by the institutional review board of American University of Beirut Medical Center. All patients received the following conditioning regimen of sequential chemotherapy: Thiotepa intravenous (IV) (5mg/kg/day) on days -13 and -12, Cyclophosphamide IV (400mg/m2/day) from day -11 to day -8 , Etoposide IV (100mg/m2/day) from day -11 to day-8, Fludarabine IV (30mg/m2/day) from day -5 to day-1, Busulfan IV (130mg/m2/day) on days -5 and -4 and ATG (thymoglobuline) IV 2,5 mg/kg on days -2 and -1 , followed by peripheral stem cells infusion on day 0. All patients characteristics, infectious complications and outcomes are listed in Table1.The primary outcomes weresafety and efficacy of this new sequential conditioning in allo-SCT. Secondary outcomes included engraftment, chimerism, acute and chronic graft versus host disease (GVHD), infections and relapse on days +30, +100 and 1 year post allo-SCT.RESULTS: After a median follow up of 7 months (range, 2-23) post-allo-SCT, all patients had neutrophil engraftment after a median time of 14 days (range, 10-20), and 13 patients had platelets engraftment after a median time of 15 days (range, 10-100). One patient failed to have platelets engraftment. At the time of last follow up, 9 patients (64%) were alive with complete remission (CR), with a median follow up of those of 7 months (range,2-23); four of whom had progressive disease (PD) at time of transplantation. Five patients who had PD at time of transplantation died. Of those, three (21%) died due to disease relapse that occurred at a median time of 152 days post allo-SCT (range, 60-296). The other two (14%) patients died because of transplant related mortality, one because of veno occlusive disease and one because of infection while were in CR. The cumulative incidence of Grade II-IV acute GVHD was 21%. Three patients (21%) developed chronic GVHD. The median progression free survival (PFS) and the median overall survival (OS) were not reached. All the complications and outcomes post allo-SCT are listed in table 1.CONCLUSIONS: Our results indicate that this sequential conditioning regimen appears to be feasible, with low TRM, allows high rate of engraftment and good disease control among high-risk patients. Further large prospective trials needed to evaluate that. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

RARE-07. EFFICACY AND SAFETY OF LAROTRECTINIB IN PEDIATRIC PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION-POSITIVE PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS

Background NTRK gene fusions are oncogenic drivers in various CNS and non-CNS tumors. Larotrectinib is a highly selective TRK inhibitor approved to treat patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across multiple non-CNS cancers (McDermott et al, ESMO 2020). We report updated data on pediatric patients with TRK fusion-positive primary CNS tumors. MethodsPatients aged <18 years with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed. ResultsBy July 2020, 26 pediatric patients with TRK fusion-positive CNS tumors were treated. Tumor histologic subtypes included high-grade glioma (n=13), low-grade glioma (n=7), glioneuronal tumor (n=2), neuroepithelial tumor (n=2), CNS neuroblastoma (n=1), and small round blue cell tumor (n=1). Median age was 7.0 years (range 1.3–16.7). The ORR was 38% (95% CI 20–59%): 3 complete responses, 7 partial responses (including 2 pending confirmation), 14 stable disease, and 2 progressive disease. The ORR in patients with high-grade glioma was 38% (95% CI 14–68%). Nineteen of 21 patients (90%) with measurable disease had tumor shrinkage. The 24-week disease control rate was 77% (95% CI 56–91%). Median duration of response (DoR), PFS and overall survival (OS) were not reached. The 12-month rates for DoR, PFS and OS were 75%, 65%, and 86%, respectively. Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events were reported for 15 patients (58%) and were Grade 3–4 in 3 patients (12%), with no discontinuations related to larotrectinib. ConclusionsIn pediatric patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated durable responses, high disease control rate, and good tolerability. These results support testing for NTRK gene fusions in pediatric patients with CNS tumors.

Efficacy and Safety of 177Lu-DOTATATE in Lung Neuroendocrine Tumors: A Bicenter study.

The purpose of this study was to assess the efficacy and safety of 177Lu-DOTATATE in patients with somatostatin receptor (SSR)-positive lung neuroendocrine tumors (NETs). Methods: This is a retrospective review of the outcome of patients with typical carcinoid (TC) and atypical carcinoid (AC), treated with 177Lu-DOTATATE at 2 ENETS Centers of Excellence. Morphologic imaging (RECIST 1.1) and 68Ga-DOTATATE PET/CT responses were assessed at 3 mo after completion of 177Lu-DOTATATE. Concordance between 2 response assessment methods was evaluated by κ statistics. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and compared by Log-rank test. Treatment-related adverse events (AEs) were graded based on Common Terminology Criteria for Adverse Events, version 5. Results: Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of 177Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted κ of 0.51 (95% CI, 0.21-0.68). Of patients with stable disease by RECIST, those with partial response on 68Ga-DOTATATE PET/CT had a longer OS than those with no response, NR versus 52 mo (95% CI, 28-64), hazard ratio 0.2 (95% CI, 0.1-0.6), P < 0.001. Most grade 3/4 AEs were reversible and the most common was lymphopenia (14%) with no incidence of myelodysplasia or leukemia. Conclusion: In patients with advanced progressive lung NET and satisfactory SSR expression, 177Lu-DOTATATE is effective and safe with a high disease control rate and encouraging PFS and OS.

Efficacy and safety of larotrectinib in adult and pediatric patients with tropomyosin receptor kinase (TRK) fusion-positive primary central nervous system tumors.

2002 Background: Neurotrophic tyrosine receptor kinase ( NTRK) gene fusions are oncogenic drivers in various tumor types, including central nervous system (CNS) tumors. Larotrectinib is a first-in-class, highly selective TRK inhibitor approved for the treatment of adult and pediatric patients with TRK fusion cancer, with an objective response rate (ORR) of 78% across 175 adult and pediatric patients with various non-CNS cancers (McDermott et al, ESMO 2020). We report data on patients with TRK fusion-positive primary CNS tumors. Methods: Patients with primary CNS tumors harboring an NTRK gene fusion enrolled in two clinical trials (NCT02637687, NCT02576431) were identified. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Response was investigator assessed. Results: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified: 19 high-grade gliomas (HGG), 8 low-grade gliomas (LGG), 2 glioneuronal tumors, 2 neuroepithelial tumors, 1 CNS neuroblastoma, and 1 small round blue cell tumor. The patients had gene fusions involving NTRK2 (n = 24; 73%), NTRK1 (n = 5; 15%), and NTRK3 (n = 4; 12%). Median age was 8.9 years (range 1.3–79.0); 26 patients were pediatric ( &lt; 18 years). Patients were heavily pre-treated with 45% having 2 or more prior lines of systemic therapy. The ORR in all patients was 30% (95% CI 16–49): 3 complete responses (all in pediatric patients), 7 partial responses (2 pending confirmation), 20 stable disease (including 15 pts &gt; 6 months), and 3 progressive disease. The ORR in patients with HGG and LGG were 26% (95% CI 9–51) and 38% (95% CI 9–76), respectively. In all patients, the 24-week disease control rate was 73% (95% CI 54–87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The median time to response was 1.9 months. Median duration of response (DoR) was not reached (95% CI 3.8–not estimable [NE]) at a median follow-up of 12.0 months. The 12-month DoR rate was 75% (95% CI 45–100). Median PFS was 18.3 months (95% CI 6.7–NE) at a median follow-up of 16.5 months. Median overall survival (OS) was not reached (95% CI 16.9–NE) at a median follow-up of 16.5 months, with a 12-month OS rate of 85% (95% CI 71–99). Duration of treatment ranged from 1.2 to 31.3+ months. Treatment-related adverse events (TRAE) were reported by 20 patients and were Grade 3–4 in 3 patients (9%). There were no treatment discontinuations due to TRAEs. Conclusions: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile. These results support testing for NTRK gene fusions in patients of all ages with CNS tumors. Clinical trial information: NCT02637687, NCT02576431.

Lenvatinib plus pembrolizumab versus lenvatinib in patients with unresectable hepatocellular carcinoma: A real world study.

e16138 Background: The combination of lenvatinib (LEN) and pembrolizumab (PEMBRO) showed promising response rates and survival in a phase 1b trial for patients with unresectable hepatocellular carcinoma (HCC). Whether LEN plus PEMBRO provides better outcomes than LEN monotherapy remains unclear. The aim of this study was to compare the outcomes of LEN plus PEMBRO versus lenvatinib monotherapy in patients with unresectable HCC in the real world setting. Methods: A total of 123 patients with unresectable HCC were retrospectively enrolled, including 61 patients with LEN monotherapy and 62 patients with LEN plus PEMBRO. We evaluated progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) by RECIST 1.1 and modified RECIST (mRECIST) criteria. Results: One hundred and one (82.1%) patients were in BCLC stage C and 81 (65.9%) patients received LEN or LEN plus PEMBRO as first line setting. During a median follow-up period of 8.0 months, 71 (57.7%) and 31 (25.2%) of patients had disease progression and death, respectively. The median PFS was 8.4 and 4.9 months in the LEN plus PEMBRO and LEN monotherapy groups, respectively (p = 0.033). The median OS was not reached in the LEN-PEM group and was 17.2 months in the LEN monotherapy group (p = 0.064). Patients with LEN plus PEMBRO had higher objective response rate (ORR: 34.4% vs 23.7% by RECIST 1.1, p = 0.277; 57.4% vs 32.2% by mRECIST, p = 0.010) and higher disease control rate (83.6% vs 62.7% by RECIST 1.1, p = 0.017; 85.2% vs 62.7% by mRECIST, p = 0.009). In subgroup patients with BCLC stage C, LEN plus PEMBRO provided significantly longer PFS (9.1 vs 4.8 months, p = 0.008), higher ORR (60% vs 33.3%, p = 0.015) and higher DCR (88% vs 60.4%, p = 0.004) by mRECIST criteria. Conclusions: LEN plus PEMBRO provides significantly better ORR, DCR and PFS then LEN monotherapy for patients with unresectable HCC.

A phase Ib study of the PI3Kδ inhibitor linperlisib in patients with advanced solid tumors.

3099 Background: Phosphatidylinositol-3 kinase (PI3K) pathways are important elements of tumor survival and progression, and PIK3C genes are often mutated or overexpressed in many cancers. Additionally, PIK3D (PI3Kδ) modulates immune cell functions in tumors, elaborating another PI3Kδ inhibition feature with a potential clinical benefit. Linperlisib, an oral and highly selective PI3Kδ inhibitor, demonstrated potent anti-tumor activity in syngeneic animals from previous research. In this Phase 1b study, the safety, tolerability, and efficacy of linperlisib is under investigation for patients with advanced solid tumors. Methods: Linperlisib was given orally once daily (QD) in 28-day cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Adverse events (AEs) were graded by NCI-CTCAE v5.0. Efficacy was assessed according to RECIST1.1 criteria. Results: As of December 28, 2020, 70 patients were enrolled in the Phase1b study, with advanced cancers, including colorectal (n = 22), breast (n = 8), lung (n = 8), kidney (n = 5), liver (n = 4), ovarian (n = 1), head and neck (n = 5), and esophageal (n = 1) cancers; sarcomas, (n = 4), small intestinal stromal tumor (n = 3), thymic (n = 2), gallbladder (n = 2), gastric (n = 4), and pancreatic (n = 1) carcinomas. The patients were heavily pretreated with an average of 4 previous lines of therapy. Among the 70 patients, the most common nonhematologic TEAEs (all grades/grade≥3) were proteinuria (37.14%/0%), elevated aspartate aminotransferase (20%/0%), nausea (20%/0%), oral mucositis (2.8%/2.8%), diarrhea (2.8%/2.8%). The most common hematological TEAEs were leukopenia (24.28%/0%) and neutropenia (17.14%/4.28%). There were no unexpected toxicities in this study. Of 42 patients evaluable for response, the overall response rate was 2.38%. Notably, the disease control rate (DCR) was 45.24% from monotherapy treatment. One patient with thymic carcinoma obtained a partial response (80.8% reduction of the target lesion), with a duration of response of more than 6 cycles. The treatment of this subject is continuing. A lung adenocarcinoma subject reached radiological stable disease associated with 13.7% reduction in the target lesion and disease control for approximately 6 months. Conclusions: In this study, the PI3K inhibitor, linperlisib exhibited a favorable safety profile as was previously seen in lymphoma patients. Monotherapy treatment with linperlisib was observed to impart a high DCR in advanced solid cancers of many types. Available data from linperlisib and other PI3K inhibitors suggests that linperlisib may limit tumor growth directly, but also by affecting the tumor immune microenvironment. With these promising indications of clinical tolerability and activity, further investigation of linperlisib alone or in key therapeutic combinations is warranted. Clinical trial information: NCT04049929.

Anlotinib plus docetaxel versus docetaxel as second-line treatment for advanced non-small cell lung cancer (NSCLC): Updated results from a phase I/II study.

e21055 Background: Second-line chemotherapy alone, such as docetaxel, is standard of care for patients (pts) with advanced NSCLC, but the efficacy is poor. Anti-angiogenic drugs plus chemotherapy had shown to significantly prolong progression-free survival (PFS) in advanced NSCLC (REVEL and LUME-LUNG1). The REVEL trial had demonstrated that East Asian pts with advanced NSCLC receiving docetaxel (60 mg/m2, not 75mg/m2) and ramucirumab had a better safety profile. Anlotinib, a novel oral multitarget tyrosine kinase inhibitor, significantly improved PFS and overall survival (OS) of advanced NSCLC in the ALTER0303 trial. In the phase I study, 10mg (QD, d1 to 14 of a 21-day cycle) was identified as the maximum tolerated dose (MTD) of anlotinib when combined with docetaxel (60mg/m2) by a 3+3 dose de-escalation exploration. Here, we presented the updated efficacy and safety of anlotinib plus docetaxel versus docetaxel as second-line treatment for driver-negative advanced NSCLC in the phase II study. Methods: This open-label, multicenter, randomized phase II study enrolled advanced NSCLC pts who had progressed after first-line platinum-based chemotherapy, without sensitizing EGFR/ALK/ROS1 alterations, and with ECOG PS 0-1. Eligible pts were randomized 2:1 to receive anlotinib (10mg, p.o, QD, d1 to 14 of a 21-day cycle) plus docetaxel (60mg/m2, q3w, 4-6 cycles) (A+D arm) or docetaxel (60mg/m2, q3w, 4-6 cycles) alone (D arm) until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included the objective response rate (ORR), the disease control rate (DCR), OS and safety. Results: From Jun. 2019 to Dec. 2020, 36 pts were enrolled, 24 pts (median age: 63.0, squamous cell carcinoma: 50.0%, ECOG PS 1: 87.5%) in the A+D arm and 12 pts (median age: 60.0, squamous cell carcinoma: 50.0%, ECOG PS 1: 83.3%) in the D arm. As of Jan. 20, 2021, the median PFS were 6.2 months (95% Cl: 0.00-12.82) in the A+D arm vs 1.4 months (95% Cl: 0.71-2.09) in the D arm (HR: 0.30; 95% Cl: 0.11-0.78, p = 0.007), which remain immature because of the shorter follow-up time. The median OS was not reached. For tumor response, 32 pts were evaluable. The ORR was 27.3% in the A+D arm vs 0% in the D arm (p = 0.142), and the A+D arm showed a significantly higher DCR than the D arm (100.0% vs 50.0%, p = 0.001). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 33.3% (A+D arm) and 0.0% (D arm). The most commonly reported grade 3/4 TRAEs in the A+D arm included neutropenia (8.3%, 2/24), leukopenia (8.3%, 2/24), oral mucositis (8.3%, 2/24) and hypertension (8.3%, 2/24). No grade 5 TRAEs or deaths were observed. Conclusions: Anlotinib plus docetaxel continues to show the better clinical benefit as second-line treatment for driver-negative advanced NSCLC. The safety profile was manageable and consistent with previously reported studies. The longer follow-up time is required. Clinical trial information: NCT03726736.

Residual of circulating tumor DNA (ctDNA) indicated therapeutic efficacy of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC).

e21207 Background: The synergetic effect of ICIs plus chemotherapy has been demonstrated in first line setting for patients with advanced NSCLC. As previously reported, sintilimab plus docetaxel in advanced Chinese NSCLC pts who had failed first-line chemotherapy showed encouraging efficacy and tolerable safety profile. This exploratory study aims to investigate putative biomarker(s) predicting therapeutic response and long-term outcome for eligible patients. Methods: Advanced NSCLC pts who had failed standard platinum doublet without receiving any ICIs before would receive docetaxel (75mg/m2, day 1) plus sintilimab (200mg, day 3) every 3 weeks for 4-6 cycles followed by sintilimab maintenance until disease progression, unacceptable toxicity, or up to 2 years. Thirty-nine eligible patients received comprehensive genomic profiling of circulating tumor DNA (ctDNA) via a 448-gene panel before treatment. ctDNA from twenty-three patients were dynamically assessed after two courses (at 6th week). Eventually, 22 patients were enrolled into analysis, one patient was lost. White blood cells were used to filter germline variants from ctDNA sequencing data. Results: Of 22 patients with paired ctDNA profiling results at 6th week, 11 patients (50%) were defined as ctDNA residual due to presence of ≥2 somatic variants; Another 11 patients (50%) who had ≤1 somatic variant were defined as non-ctDNA residual. Significant difference of best objective response rate (ORR) (63.64% vs 0%, P=0.0039, two-sided Fisher’s Exact Testing for non-ctDNA residual vs ctDNA residual patients) was observed between these two populations. And numerically higher disease control rate (DCR) was seen in non-ctDNA residual patients (100% vs 63.64%, non-ctDNA residual vs ctDNA residual). Further, patients with ctDNA residual after 2 courses of sintilimab plus docetaxel (at 6th week) displayed higher risk of disease progression [Hazard Ratio (95%CI), 9.91(2.09-46.97), P=0.0038] and inferior prognosis (median PFS, ctDNA residual vs non-ctDNA residual, 3.0 months vs NR, P=0.0007). In addition, mutations of EGFR and LRP1B were enriched in ctDNA residual group. Especially, LRP1B gene mutations associated with shorter PFS period, which should be further investigated. Conclusions: Residual of ctDNA at 6th week was able to indicate inferior response to sintilimab plus docetaxel in patients with previously treated advanced NSCLC. Further validation of ctDNA residual as a robust predictive biomarker is warranted. [Table: see text]

Hepatic Arterial Infusion Chemotherapy of Oxaliplatin, Fluorouracil, and Leucovorin With or Without Sorafenib as Initial Treatment for Advanced Hepatocellular Carcinoma.

PurposeOur previous study showed that hepatic arterial infusion chemotherapy (HAIC) using oxaliplatin, fluorouracil, and leucovorin (FOLFOX) plus sorafenib provided a significant survival benefit over sorafenib for advanced hepatocellular carcinoma. However, it is unclear whether the survival benefit should be attributed to the synergism between HAIC and sorafenib or just HAIC alone. We aim to compare HAIC using FOLFOX plus sorafenib with HAIC alone in patients with advanced hepatocellular carcinoma.Materials and MethodsThis was a retrospective study including 225 eligible patients treated with HAIC using FOLFOX (HAIC alone group, n=126, oxaliplatin 85 mg/m², leucovorin 400 mg/m², fluorouracil bolus 400 mg/m² and 2400 mg/m² for 46 hours, every 3 weeks) alone or HAIC plus sorafenib (soraHAIC group, n=99, sorafenib 400 mg twice daily). Survival curves were calculated by the Kaplan-Meier method, and propensity-score matching was used to reduce bias.ResultsThe soraHAIC group showed a longer overall survival (12.9 [95% CI, 10.4-15.4] vs. 10.5 [95% CI, 9.5-11.5] months, HR=0.71 [95% CI, 0.53-0.96]; P=0.025), a better progression free survival (7.0 [95% CI, 5.3-8.8] vs. 5.3 [95% CI, 3.5-7.1] months, HR=0.76 [95% CI, 0.58-0.99]; P=0.046), and a higher disease control rate (RECIST 1.1: 74.8% vs. 61.1%, P=0.030) than the HAIC alone group. In multivariate analysis, soraHAIC was an independent favor factor for survival. In terms of the grade 3/4 adverse event, hand–foot skin reaction was more frequent in the soraHAIC group than the HAIC alone group. In the propensity-score matched cohorts (93 pairs), the overall survival, the progression free survival and disease control rates in the soraHAIC group were also better than those in the HAIC group (P<0.05).ConclusionHAIC plus sorafenib may improve overall survival and progression free survival compared with HAIC alone as initial treatment for advanced hepatocellular carcinoma.

Chemotherapy-Free Management of Follicular and Marginal Zone Lymphoma.

Many patients with follicular (FL) or marginal zone lymphoma (MZL) are not eligible to receive immunochemotherapy due to advanced age or comorbidities. Recent innovations in the treatment of these indolent lymphomas provide options for multiple lines of chemotherapy-free management. More research is needed to determine which older patients are best served by a chemotherapy-free approach in the context of geriatric vulnerabilities. In the first line, regardless of disease burden, rituximab monotherapy can provide high rates of disease control with minimal toxicity, while judicious use of brief maintenance extends the duration of response. Radioimmunotherapy using ibritumomab tiuxetan is an effective and safe post-rituximab consolidation for older patients who have <25% bone marrow involvement. The combination of rituximab and lenalidomide, although “chemotherapy-free”, does not improve tolerability over immunochemotherapy. However, studies support lower doses and shorter duration of lenalidomide exposure as a means to improve safety without materially compromising efficacy for older individuals. Extranodal MZL can often be effectively controlled with low-dose radiation therapy, and splenic MZL has excellent outcomes with rituximab monotherapy. For many patients with relapsed FL/MZL, simple retreatment with anti-CD20 antibodies will prove sufficient. Other currently available options for relapsed/refractory disease include ibritumomab tiuxetan, lenalidomide with rituximab, umbralisib as a potentially less toxic PI3K inhibitor, ibrutinib (for MZL), and tazemetostat (for FL, especially with EZH2 mutation). Emerging data with novel forms of immunotherapy (antibody-drug conjugates like polatuzumab vedotin or loncastuximab tesirine; T-cell-engaging bispecific antibodies like mosunetuzumab or epcoritamab; and chimeric antigen receptor CAR T-cells like axicabtagene ciloleucel) suggest that immune-directed approaches can produce very high and potentially durable responses in FL/MZL with limited toxicities, further obviating the need for chemotherapy.

Abstract No. 8 Yttrium-90 radioembolization in unresectable intrahepatic cholangiocarcinoma: a 17-year single-institution study

The purpose of this study was to evaluate the safety, efficacy, and survival following radioembolization (Y90) for unresectable intrahepatic cholangiocarcinoma (ICC). Our hypothesis was Y90 would provide high antitumor response with a tolerable safety profile. An IRB-approved retrospective analysis was performed in 138 consecutive patients with ICC treated with Y90 from 2004 to 2020. Primary outcomes were clinical and biochemical toxicities by CTCAE (version 5.0) and tumor response by World Health Organizing (WHO) criteria. Secondary outcomes were time-to-progression (TTP) and overall survival (OS) by the Kaplan-Meier method with censoring to resection/transplantation. Univariate and multivariate survival analyses were performed with log-rank tests and Cox proportional-hazards model, respectively. Baseline characteristics included solitary tumor in 56 (40.6%), unilobar distribution in 59 (42.8%), tumor burden < 25% in 96 (69.6%), extrahepatic disease in 48 (34.8%), and prior chemotherapy in 56 (40.6%). Grade 3+ clinical toxicities occurred in 10 (7.5%). Grade 3 bilirubin and alkaline phosphatase toxicities occurred in 4 (3.2%) and 2 (1.6%), respectively. Best response rates (WHO) were complete response in 3 (2.3%), partial response in 46 (34.9%), stable disease in 74 (56.1%), and progressive disease in 9 (6.8%) patients. Median index lesion TTP was not reached. Median intrahepatic TTP and extrahepatic TTP were 5.9 months (95% CI, 4.1-8.4) and 13.1 months (95% CI, 7.4-19.6), respectively. Eleven patients (8.0%) were downstaged to resection with OS of 41.8 months (95% CI, 16.1-NE). Additionally, three patients (2.2%) were transplanted. Median time to recurrence was 26.6 months (95% CI, 4.4-NE). Median OS for the entire cohort was 13.8 months (95% CI, 10.5-16.0). On multivariate OS analysis, solitary ICC (P< 0.001), no prior chemotherapy (P = 0.02), tumor burden < 50% (P = 0.03), no tumor thrombus (P = 0.004), and higher serum albumin (P = 0.01) were positive prognosticators. Y90 has an acceptable safety profile in a large cohort of patients with heterogenous treatment history and disease burden. High local disease control rates and downstaging in select patients supports the therapeutic role of Y90 for unresectable ICC.

Association between Low-Grade Chemotherapy-Induced Peripheral Neuropathy (CINP) and Survival in Patients with Metastatic Adenocarcinoma of the Pancreas

The combination of nab-paclitaxel and gemcitabine demonstrated greater efficacy than gemcitabine alone but resulted in higher rates of chemotherapy-induced peripheral neuropathy (CINP) in patients with metastatic pancreatic cancer (mPC). We aimed to evaluate the correlation between the development of treatment-related peripheral neuropathy and the efficacy of nab-P/Gem combination in these patients. mPC patients treated with nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 as a first-line therapy were included. Treatment-related adverse events, mainly peripheral neuropathy, were categorized using the National Cancer Institute Common Toxicity Criteria scale, version 4.02. Efficacy outcomes, including overall survival (OS), progression-free survival (PSF), and disease control rate (DCR), were estimated by the Kaplan–Meier model. A total of 153 patients were analyzed; of these, 47 patients (30.7%) developed grade 1–2 neuropathy. PFS was 7 months (95% CI (6–7 months)) for patients with grade 1–2 neuropathy and 6 months (95% CI (5–6 months)) for patients without peripheral neuropathy (p = 0.42). Median OS was 13 months (95% CI (10–18 months)) and 10 months (95% CI (8–13 months)) in patients with and without peripheral neuropathy, respectively (p = 0.04). DCR was achieved by 83% of patients with grade 1–2 neuropathy and by 58% of patients without neuropathy (p = 0.03). In the multivariate analysis, grade 1–2 neuropathy was independently associated with OS (HR 0.65; 95% CI, 0.45–0.98; p = 0.03). nab-P/Gem represents an optimal first-line treatment for mPC patients. Among possible treatment-related adverse events, peripheral neuropathy is the most frequent, with different grades and incidence. Our study suggests that patients experiencing CINP may have a more favorable outcome, with a higher disease control rate and prolonged median survival compared to those without neuropathy.

Do we need skin toxicity? Association of immune checkpoint inhibitor and tyrosine kinase inhibitor-related cutaneous adverse events with outcomes in metastatic renal cell carcinoma.

Skin toxicity is a common, expected side effect of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) used for metastatic renal cell carcinoma (mRCC). We evaluated the association between skin toxicity and clinical efficacy outcomes of these agents in mRCC patients. Data were obtained from patients with mRCC treated with TKIs and/or ICIs from 2016-2019 at a referral hospital in Mexico City. Clinical outcomes were compared among patients who developed treatment-related cutaneous adverse events (AEs) and those without skin toxicity. Thirty-five patients with mRCC were identified who were treated with sunitinib (51.4%), nivolumab plus cabozantinib (28.6%), nivolumab monotherapy (17.1%), or ipilimumab plus nivolumab plus cabozantinib (2.9%). Any grade skin toxicity was seen in 65.7% of patients. With a median follow-up of 14months, radiological responses were as follows: 48.6% stable disease, 25.7% partial response, and 2.8% complete response. Compared to subjects without skin toxicity, patients who developed cutaneous AEs had higher disease control rate 91.3% vs. 50.0% (P=0.019) and superior 12-month overall survival rate 91% vs. 67% (P=0.01), respectively. There was a trend toward improved median progression-free survival (16months vs. 5months, P=0.13). Grade 1-2 cutaneous toxicity was found to be predictive for disease control, with HR 2.72 (95% CI 1.1-6.71, P=0.030), and all grade cutaneous toxicity was prognostic of overall survival, with HR 0.18 (95% CI 0.04-0.91, P=0.039). Cutaneous AEs are associated with improved overall survival and response in patients with mRCC treated with immunotherapy and/or TKIs.

Efficacy of FOLFOX Chemotherapy in Metastatic Enteropancreatic Neuroendocrine Tumors.

FOLFOX (5-Fluorouracile and oxaliplatin) exhibits promising activity in advanced well-differentiated neuroendocrine tumors (NETs). This retrospective study aimed to analyze the outcome of metastatic enteropancreatic NETs patients treated with FOLFOX. We retrospectively identified patients treated with FOLFOX for NETs of enteropancreatic or unknown origin among those referred to our Regional Multidisciplinary Tumor Board. Among 48 patients, most often pancreatic NETs (n=33, 68.8%), the median Ki67 index was 10%. The median number cycle of FOLFOX was 6 and median follow-up was 34.8 months. Disease control rate (DCR) was 83.3%. Median PFS and OS were 12.6 and 29.4 months respectively. Median chemotherapy break was 14.1 months. No significant difference was observed between PFS and the following criteria: Ki67 index, primary tumor site, alkaline phosphatase levels, primary tumor surgery and 18F-FDG PET positivity. FOLFOX exhibits a high DCR and a short duration of treatment with a relative long chemotherapy break in patients with metastatic enteropancreatic NETs.

A Pilot Study Analyzing the Clinical Utility of Comprehensive Genomic Profiling Using Plasma Cell-Free DNA for Solid Tumor Patients in Japan (PROFILE Study).

The clinical utility of plasma cell-free DNA in precision cancer medicine has not been established. A pilot study was conducted to investigate the clinical utility of comprehensive genomic profiling by liquid biopsy in a Japanese population. In this PROFILE study, 102 patients with advanced solid tumors who showed progression with standard systemic therapy underwent liquid biopsy between August 2017 and February 2020. Liquid biopsy was performed using Guardant360. Of the 102 patients, 56 were women, and the median age was 65 years. Regarding the types of cancer, 31 were hepatobiliary and pancreatic cancer, 17 were gastrointestinal cancer, and 13 were breast cancer. Frequently altered genes were TP53 (53.9%, 46/102), KRAS (25.5%, 26/102), PIK3CA (19.6%, 20/102), and EGFR (17.6%, 18/102). At least one genetic aberration was detected in 92 patients (90.2%). Actionable mutation was discovered in 88 patients (86.3%), and 67 patients (65.7%) were clinical trial candidates. Of the 102 patients, 22 (21.6%) were able to receive biomarker-matched therapy. Their best responses were as follows: 1 complete response, 3 partial responses, 7 stable diseases, and 11 progressive diseases. Additionally, the treated patients were divided on the basis of matching scores (≥ 50% vs. < 50%). The patients were divided into high and low groups. The high group had a higher disease control rate (DCR) of 75% compared with 20% in the low group (P = 0.010). The results indicate that liquid biopsy is useful for identifying actionable mutations associated with the clinical response of selected patients.

Therapeutic Outcomes and Prognostic Factors of Unresectable Intrahepatic Cholangiocarcinoma: A Data Mining Analysis.

Prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is unsatisfactory. Tumor, host, and treatment factors including hepatic arterial infusion chemotherapy (HAIC) are intricately involved in the progression of ICC. We aimed to identify profiles associated with disease control rate (DCR) and the prognosis of patients with unresectable ICC by decision tree analysis. We analyzed 31 consecutive patients with unresectable ICC (median age, 71 years; the male ratio was 58.1%). Stage IVB occupied 51.6% of patients, and 38.7% and 58.1% of patients were treated with gemcitabine plus cisplatin combination therapy and HAIC, respectively. Profiles associated with prognosis as well as DCR were investigated by decision tree analysis. The median survival time (MST) of the patients was 11.6 months, and the DCR was 70.9%. Multivariate correlation analysis showed that albumin levels and WBC levels were significantly correlated with survival time (albumin, ρ = 0.3572, p = 0.0485; WBC, ρ = −0.4008, p = 0.0280). In decision tree analysis, WBC level was selected as the initial split variable, and subjects with WBC levels of 6800/μL or less (45.1%) showed a long survival time (MST 476 days). We also demonstrated that the profile associated with the highest DCR was “less than 4.46 mg/dL of CRP levels and treatment with HAIC”. We demonstrated a new prognostic profile for ICC patients, which consisted of WBC and CRP levels. Moreover, we demonstrated that HAIC was associated with better disease control in ICC patients with low CPR levels. Thus, these new profiles may be useful for the management of ICC patients.

Phenotypic and Proteomic Analysis Identifies Hallmarks of Blood Circulating Extracellular Vesicles in NSCLC Responders to Immune Checkpoint Inhibitors.

Simple SummaryPurpose of this study was to investigate the prognostic and predictive role of blood circulating extracellular vesicles (EVs) in patients with advanced non-small cell lung cancer treated with immunotherapy. A newly optimized flow cytometry protocol was applied for identification and subtyping of blood circulating EVs in a total cohort of 59 NSCLC patients, which included 31 patients treated with anti-PD-1/PD-L1 agents and 28 patients treated with traditional chemotherapy. Our results show that pre-treatment concentration of blood circulating endothelial-derived EVs was correlated with overall survival and clinical response in patients treated with immunotherapy. Additionally, proteomic analysis of purified blood circulating EVs indicated differences in EV protein cargo between responders and non-responders to immunotherapy. These findings may pave the way to the identification of novel immunotherapy biomarkers in patients with advanced NSCLC.Immune checkpoint inhibitors (ICIs) induce durable clinical responses only in a subset of advanced non-small cell lung cancer (NSCLC) patients. There is a need to identify mechanisms of ICI resistance and immunotherapy biomarkers to improve clinical benefit. In this study, we evaluated the prognostic and predictive value of circulating endothelial and leukocyte-derived extracellular vesicles (EV) in patients with advanced NSCLC treated with anti-PD-1/PD-L1 agents. In addition, the relationship between total blood circulating EV proteome and response to ICIs was investigated. An optimized flow cytometry method was employed for the identification and subtyping of blood circulating EVs in 59 patients with advanced NSCLC. Blood samples were collected from patients receiving anti-PD-1/PD-L1 inhibitors (n = 31) or chemotherapy (n = 28). An exploratory proteomic analysis of sorted blood EVs was conducted in a subset of patients. Our results show that a low blood concentration of circulating endothelial-derived EVs before treatment was strongly associated to longer overall survival (p = 0.0004) and higher disease control rate (p = 0.045) in patients treated with ICIs. Interestingly, shotgun proteomics revealed that EVs of responders to anti-PD-1 therapy had a specific protein cargo before treatment. In addition, EV protein cargo was specifically modulated during immunotherapy. We identified a previously unknown association between circulating endothelial-derived extracellular vesicle concentration and immunotherapy-related clinical outcomes. We also observed differences in circulating extracellular vesicle proteome according to anti-PD-1-based treatment response in NSCLC patients. Overall, these results may contribute to the identification of novel circulating biomarkers for rational immunotherapy approaches in patients affected by NSCLC.